Terazosin capsules

ABSTRACT

A capsule dosage form containing solid form of terazosin in a solid carrier is disclosed. The capsule dosage form is stable under accelerated stability conditions and therapeutically equivalent to known liquid-filled terazosin capsules.

SUMMARY

Terazosin is administered to subjects in filled gelatin capsulescontaining a solid fill. The capsules are bioequivalent to a referenceliquid-filled terazosin capsule dosage form, but have an advantageousshelf life and are simpler to manufacture.

BACKGROUND

Terazosin, especially in its salt forms, is a well-known medicamentwhich is useful in the treatment of hypertension and benign prostatichyperplasia. For example, U.S. Pat. No. 4,026,894 discloses thehydrochloride salt of terazosin as well as its use in pharmaceuticalformulations used for the treatment of hypertension, and U.S. Pat. No.4,251,532 discloses the compound terazosin hydrochloride dihydrate andits use as a pharmaceutical active ingredient.

The U.S. Food and Drug Administration (FDA) first approved terazosinhydrochloride dihydrate for sale in the United States in 1987 as atablet formulation which was marketed by Abbott Laboratories under thetradename HYTRIN.

U.S. Pat. No. 5,294,615 describes a soft gelatin capsule dosage formcontaining terazosin hydrochloride in a non-aqueous liquid carrier andindicates that polyethylene glycol is a preferred non-aqueous liquidcarrier. In 1994, the FDA approved a soft gelatin capsule formulationcontaining the active ingredient suspended in a non-aqueoLs liquidcarrier composed primarily of polyethylene glycol with some glycerinepresent.

The present invention relates to the surprising discovery that a stable,therapeutic equivalent of known liquid-filled capsule dosage forms ofterazosin hydrochloride is prepared simply and effectively by replacingthe liquid carrier with a solid carrier. Thus, the present inventionrelates to solid-filled terazosin hydrochloride capsules which arestable under accelerated conditions and which are therapeuticequivalents of the liquid-filled capsule dosage forms.

As therapeutic equivalents, the inventive solid-filled terazosinhydrochloride capsules are surprisingly bioequivalent to the FDAapproved liquid-filled terazosin hydrochloride capsules. It is a greatadvantage that the inventive formulations are bioequivalent to the FDAapproved liquid-filled terazosin hydrochloride capsules because theinventive formulations can be marketed as generic equivalents of theapproved product without performing new safety and efficacy studies,which add considerably to the cost of obtaining FDA approval to market adrug product.

DETAILED DESCRIPTION

The present invention relates to a pharmaceutical capsule dosage formwhich comprises a pharmaceutically effective amount of terazosin in theform of a solid pharmaceutically acceptable salt, or solvate thereof,and a solid carrier, which capsule dosage form is bioequivalent to areference terazosin capsule, which reference terazosiin capsule is aliquid-filled capsule comprising an equivalent amount of terazosin and anon-aqueous liquid carrier. Thus, the present invention relates to animproved, pharmaceutical capsule dosage form containing terazosin, inthe form of a salt or solvate thereof, which dosage form isbioequivalent to a liquid-filled terazosin capsule comprising anequivalent amount of terazosin and a nonaqueous liquid carrier, whereinthe improvement consists essentially of replacing the nonaqueous liquidcarrier with a pharmaceutically acceptable carrier which is a solid at25° C.

In particular, the present invention relates to a pharmaceutical capsuledosage form which is stable under accelerated stability conditions.Accordingly, the present invention relates to a stable pharmaceuticalsolid-filled capsule dosage form which comprises a pharmaceuticallyeffective amount of terazosin in the form of a solid pharmaceuticallyacceptable salt, or solvate thereof, and a solid carrier, whichsolid-filled capsule dosage form is therapeutically equivalent to areference liquid-filled terazosin capsule comprising an equivalentamount of terazosin and a non-aqueous liquid carrier, and whichsolid-filled capsule dosage form has an average dissolution at 30minutes measured according to U.S.P. Method II at 50 r.p.m. in water ofat least 85 percent of the label amount with no individual capsule below80 percent of the label amount after being maintained in a high densitypolyethylene bottle closed with a screw cap at about 40° C. and 85percent relative humidity for twelve weeks.

Pharmaceutical capsule dosage forms are well-known in the art. Ingeneral, a capsule dosage form consists essentially of a shell and afill, which is encapsulated by the shell and contains the activeingredient, in this case terazosin in the form of a salt or solvate, aswell as carrier. The shell is usually primarily composed of gelatin andcan contain additional ingredients such as a plasticizer, likeglycerine, sorbitol or propylene glycol, an opacifier, a coloring agent,a flavoring agent and/or a preservative. Generally, capsule shells areclassified as either soft elastic capsules, such as those described inU.S. Pat. No. 5,294,615 which have a plasticizer, or hard capsuleshells, which generally do not contain any appreciable amount of aplasticizer. Preferably, the inventive dosage forms have a hard capsuleshell due to the relative ease of manufacture.

In this application, when referring to a solid-filled capsule dosageform, "stable" means that the capsule dosage form has an expiration datewhich permits it to be sold for a period of at least two years from itsmanufacture.

A pharmaceutically effective amount of terazosin is an amount which isappropriate in a dosage form useful to treat hypertension or benignprostate hyperplasia. In general, from 1 to 15 mg of terazosin is apharmaceutically effective amount. Currently, terazosin hydrochloride ismarketed in dosage forms containing 1, 2, 5, and 10 mg equivalent ofterazosin.

Solid pharmaceutically acceptable salts and solvates of terazosininclude any non-toxic acid addition salt which is water-soluble andsolid at room temperature, in particular the hydrochloride salt inanhydrous form, including polymorphic forms and nixtures thereof, or asa non-toxic solvate, such as terazosin hydrochloride dihydrate.

In this application, the expression "therapeutically equivalent to areference liquid-filled terazosin capsule" is intended to mean that theinventive capsule dosage form is a generic equivalent of the referenceliquid-filled terazosin capsule and as such is rated an AB therapeuticequivalent of the reference liquid-filled capsule by the FDA wherebyactual or potential bioequivalence problems have been resolved withadequate in vivo and/or in vitro evidence supporting bioequivalence.Accordingly, the solid-filled capsule dosage form is the subject of anAbbreviated New Drug Application (ANDA) filed under section 505(j) ofthe Food Drug and Cosmetic Act (FDCA) (21 U.S.C. 355(j)) which containsa bioequivalence study wherein the reference drug is a liquid-filledterazosin capsule containing the active ingredient dissolved orsuspended in a non-aqueous liquid carrier as the fill.

The expression "bioequivalent" or "bioequivalence" is a term of art andis intended to be defined in accordance with Approved Drug Products withTherapeutic Equivalence Evaluations, 15th Edition, pages vii-xvii, whichis published by the U.S. Department of Health and Human Services, and iscommonly known as the "Orange Book". Bioequivalence of differentformulations of the same drug substance involves equivalence withrespect to the rate and extent of drug absorption. The extent and rateof absorption of the test formulation is compared to a referenceformulation in order to determine whether the two formulations arebioequivalent. The standard bioequivalence study is conducted incrossover fashion by extensive testing which includes administeringsingle doses of the test and reference drugs to a number of volunteers,usually 12 to 24 healthy normal adults, and then measuring the blood orplasma levels of the drug over time. The pharmacokinetic characteristicsof the concentration-time curve, such as the maximum observed plasmaconcentration (C_(max)), the time to reach C_(max), and the area underthe plasma concentration versus time curve (AUC), are examined bystatistical procedures which are well-established in the field ofpharmacokinetics. Two formulations whose rate and extent of absorptiondiffer by -20%/+25% or less are generally considered to bebioequivalent. Detailed guidelines for establishing the bioequivalenceof a formulation with a reference formulation have been published by theFDA Office of Generic Drugs, Division of Bioequivalence.

The expression "solid carrier" means that the overall physical form ofthe filling of the capsule is in solid form at room temperature.Generally, the filling is a powder which has been formed into acapsule-shaped slug at low compression.

The expression "liquid-filled" means that the overall physical form ofthe filling is a liquid at room temperature. The expression"liquid-filled" is intended to include suspensions or mixtures ofliquids and solids which have the overall characteristics of a liquid.

An "equivalent amount of terazosin" means the same amount of terazosinbase. Thus, by weight, it requires less anhydrous terazosinhydrochloride than terazosin hydrochloride dihydrate to have anequivalent amount of terazosin. Generally, the inventive capsules havean equivalent amount of terazosin of 1 mg, 2 mg, 5 mg or 10 mg.

The expression "non-aqueous liquid carrier" is defined according to U.S.Pat. No. 5,294,615, which is here incorporated by reference. In general,liquid carriers containing a major portion a liquid polyethylene glycol,for example, those having a molecular weight between about 200 and about600, alone or combined with additives, like a viscosity-building agentor glycerine, are described as suitable non-aqueous liquid carriers.

The present solid-filled capsule dosage form is stable based onaccelerated stability studies. Accelerated stability studies arewell-known in the pharmaceutical formulation sciences. In general, thecapsules are maintained at about 40° C. and 85 percent relative humidityfor up to twelve weeks in a high density polyethylene (HDPE) bottleclosed with a screw cap and the release rate of the capsule is measuredby in vitro dissolution testing. Since accelerated stability studies aregenerally predictive of the stability of a formulation under normalconditions, for example, by use of the Arrhenius rate equation, suchstudies are used to determine the appropriate expiration dating for theformulation. If the formulation performs well in accelerated stabilitystudies, no further testing is usually required to establish anadvantageous expiration period. If the dissolution slows significantlyafter storage, the accelerated stability study does not support anadvantageous expiration period. In general, it is a great advantage ifan expiration period of at least 24 months is established by anaccelerated stability study.

In general, the average dissolution at 30 minutes measured according toU.S.P. Method II at 50 r.p.m. in water for 6 randomly selected capsulesof the present invention, which capsules were maintained at about 40° C.and 85 percent relative humidity for twelve weeks in a high densitypolyethylene (HDPE) bottle closed with a screw cap, is at least 85percent of the label amount, with no individual capsule below 80 percentof the label amount, the label amount being the amount of terazosin baselisted on the label, for example, a 5 mg capsule has a label amount of 5mg of terazosin. Preferably, the average dissolution at 30 minutes is atleast 90 percent of the label amount with no individual capsule below80, preferably 85, percent of the label amount. Most preferably, theaverage dissolution at 30 minutes is at least 90, preferably 95, percentof an initial dissolution; the initial dissolution being the resultobtained by testing capsules from the same lot under identicalconditions; except that the initially tested capsules are not subjectedto accelerated stability conditions. Thus, the average. dissolution ofthe inventive capsule dosage form remains virtually constant over time,even after being stored under accelerated conditions for 12 weeks.Capsules showing the results described above in accelerated stabilitystudies are generally expected to be stable under normal conditions forat least two years.

The present solid-filled capsules are bioequivalent to a referenceliquid-jilled terazosin capsule comprising an equivalent amount ofterazosin and a non-aqueous liquid carrier. Preferably, the liquidcarrier comprises a major portion, such as 80 to 100% by weight, of aliquid polyethylene glycol, such as is described in U.S. Pat. No.5,294,615, especially wherein the liquid carrier further comprises aminor amount, such as from 1 to 4 weight-percent, of glycerine. Mostpreferably, the reference liquid-filled terazosin capsule is a terazosinhydrochloride capsule which is the subject of a New Drug Applicationwhich is approved by the U.S. Food and Drug Administration, especiallyNew Drug Application number N20347, which was approved on Dec. 14, 1994.

In general, the solid carrier is composed of a solid diluent along withother optional ingredients such as a disintegrant, a lubricant, a binderor a surfactant. A solid carrier used in the inventive formulations istypically composed of (a) from 70 to 100 percent by weight of a diluent;and optionally an effective disintegration-producing amount of adisintegrant and/or an effective lubricating amount of a lubricant. Forexample a typical formulation contains (a) from 70 to 100 percent byweight of a diluent, (b) from 0 to 30 percent by weight of adisintegrant; and (c) 0 to 10 percent by weight of a lubricant.Preferably, the solid carrier contain (a) from 85 to 97 percent byweight of a diluent; (b) from 1 to 10 percent by weight of adisintegrant; and (c) 0.2 to 5 percent by weight of a lubricant. Mostpreferably, the solid carrier contains (a) from 90 to 97 percent byweight of a diluent; (b) from 1 to 5 percent by weight of adisintegrant; and (c) 0.5 to 2 percent by weight of a lubricant.

Any pharmaceutically acceptable solid diluent which is non-toxic, inert,both to the active ingredient and to the capsule shell, and compressibleis useful in the solid carrier. Preferably, the diluent is readilywetted by or dissolved in an aqueous medium. In general, the diluent isa non-toxic, inert monosaccharide, disaccharide, polysaccharide, solidfatty acid, solid triglyceride, or solid phosphate, carbonate, silicate,sulfate or chloride salt. Suitable saccharide diluents include anhydrousor hydrated lactose, microcrystalline cellulose, sucrose, dextrose,sorbitol, manitol, and starch. Suitable inorganic diluents includedibasic calcium phosphate, calcium sulfate, kaolin, magnesium carbonate,magnesium oxide, talc, potassium chloride and sodium chloride and/orhydrates thereof.

Disintegrants and lubricants are well-known in the pharmaceuticalsciences. Suitable disintegrants include starch, croscarmellose sodium,crospovidone, sodium starch glycolate, croscarmellose calcium,microcrystalline cellulose and polacralin potassium, and the like.Suitable lubricants include magnesium stearate, sodium stearyl fumarate,hydrogenated vegetable oil, hydrogenated castor oil, hydrogenatedcottonseed oil, stearic acid and calcium stearate, and the like.

It is possible for certain ingredients to serve more than one functionin the formulation, for example, microcrystalline cellulose and starcheach function as both diluent and as a disintegrant.

In addition to the diluent, disintegrant and lubricant, solid carriersaccorcing to the present invention can also include a binder, such aspovidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose,hydroxyethyl cellulose, ethylcellulose and sodium alginate, as well asother pharmaceutical excipients, such as glidants and surfactants, liketalc, colloidal silicon dioxide, polyethylene glycol, sodium laurylsulfate, polysorbate, docusate sodium.

It is important for the solid carrier to contain only excipients whichare ineart to both the active ingredient and to the capsule shell. Withregard to the capsule shell, inert excipients are those which do notpromote cross-linking in the capsule shell. Such cross-linking producingexcipients are well-known in the pharmaceutical formulation sciences andare generally those which degrade by releasing formaldehyde. Thus, theinert solid carrier is a non-formaldehyde-releasing solid carrier.

The present invention further relates to a method of administering atherapeutically effective amount of terazosin to a human subject, whichcomprises producing a plasma concentration of terazosin in the subjecthaving both a maximum concentration (C_(max)) and an area under aplasma-concentration vs. time curve (AUC) within the range from -20% to+25% of that produced by a reference liquid-filled terazosin capsule,which contains an equivalent amount of terazosin in a non-aqueous liquidcarrier, by administering a solid-filled capsule dosage form whichconsists essentially of a pharmaceutically effective amount of terazosinin the form of a solid pharmaceutically acceptable salt, or solvatethereof, and a solid carrier to the subject; especially wherein thereference capsule is the subject of approved New Drug Application numberN20347. Preferably, the terazosin is present in the form of anhydrousterazosin hydrochloride or terazosin hydrochloride dihydrate.

In addition, the present invention relates to a method of formulating astable therapeutic equivalent of a reference liquid-filled terazosincapsule, which comprise, the steps of (a) preparing a solid-filledcapsule dosage form consisting essentially of a pharmaceuticallyeffective amount of terazosin in the form of a solid pharmaceuticallyacceptable salt, or solvate thereof, and a solid carrier, whichsolid-filled capsule dosage form has an average dissolution at 30minutes measured according to U.S.P. Method 11 at 50 r.p.m. in water ofat least 85 percent of the label amount with no individual capsule below80 percent of the label amount after being maintained in a high densitypolyethylene bottle closed with a screw cap at about 40° C. and 85percent relative humidity for twelve weeks; and (b) establishing thatthe solid-filled capsule dosage form is a therapeutic equivalent of thereference liquid-filled terazosin capsule by conducting a bioequivalencestudy which demonstrates that administration of the solid-filled capsuledosage form to a human subject produces both a maximum concentration(C_(max)) and an area under a pleisma-concentration vs. time curve (AUC)within the range from -20% to +25% of that produced by the referenceliquid-filled terazosin capsule.

The following examples further illustrate, but do not limit, the presentinvention.

EXAMPLE 1

Capsules containing 5 mg of terazosin were prepared by blending thefollowing ingredients according to standard methods and encapsulatingthe formulation in #3 gelatin capsules.

    ______________________________________    Ingredient          mg/dose    ______________________________________    Terazosin HCl Anhydrous                        5.471    Lactose Monohydrate, NF                        174.529    Microcrystalline Cellulose, NF                        28.000    Crospovidone, NF    14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        225.000    ______________________________________

The rate and extent of terazosin absorption under fasting conditions ofthe capsules described above was compared with the rate and extent ofterazosin absorption of the FDA-approved terazosin hydrochloride capsulecontaining the equivalent amount of terazosin base (approved on Dec. 14,1994 under application N20347 and sold by Abbott Laboratories under thetradename HYTRIN Capsules, 5 mg) measured under identical conditions ina single dose, randomized, two-period, two-treatment, two-sequencecrossover study in a group of healthy adult male volunteers. The studydemonstrates that the above-described capsule formulation isbioequivalent to the liquid-filled FDA-approved capsule containing theequivalent amount of terazosin base in accordance with GuidanceStatistical Procedures for Bioequivalence Studies Using a Standard TwoTreatment Crossover Design prepared by the FDA Division ofBioequivalence because it meets the log transformed confidence intervalsof 0.8-1.25 for both AUC and C_(max). In vitro studies furtherdemonstrate that capsules similar to those described above containing 1mg, 2 mg and 10 mg of terazosin base are also bioequivalent to with theFDA-approved terazosin hydrochloride capsule containing the equivalertamount of terazosin base. The 1 mg, 2 mg and 10 mg capsules contain theabove ingredients in the amounts stated above, but adjust the amount ofterazosin and lactose monohydnate according to the formula terazosinHCI+lactose monohydrate≈180 mg.

EXAMPLE 2

Capsules prepared according to Example 1 were subjected to anaccelerated stability study wherein HDPE bottles containing 100 or 1000capsules were closed with a screw cap and stored at 40° C. and 85%relative humidity for a period of from 1 to 12 weeks. After the storageperiod, a sample of capsules was subjected to dissolution testingaccording to U.S.P. Method II (paddles) at 50 rpm in 900 ml of water for30 minutes. The average results are reported in the following table.

                  TABLE 1    ______________________________________    Accelerated Stability    Dissolution Test (% of label - average of 6 capsules)    1 mg          2 mg       5 mg      10 mg    bottle count            100    1000   100  1000  100  1000 100  1000    ______________________________________    initial 102    102    100  100   100  100  99   99    4 week  105    105    98   98    99   101  98   99    8 week  99     100    100  98    100  100  100  98    12 week 99     99     100  101   100  101  98   98    ______________________________________

No individual capsule showed a dissolution below 95% at 4 weeks, 91% at8 weeks, and 88% at 12 weeks.

The accelerated stability study supports a two year expiration date forthe solid-filled capsules described above.

EXAMPLE 3

The following formulations for capsules containing terazosinhydrochloride equivalent to 5 mg of terazosin are prepared by blendingthe ingredients according to standard methods. Capsules containing 1 mg,2 mg and 10 mg of terazosin are prepared by encapsulating a proportionalamount of the capsule fill.

    ______________________________________    Ingredient          mg/dose    ______________________________________    1A.    Terazosin HCl Anhydrous                        5.471    Lactose Monohydrate, NF                        88.529    Microcrystalline Cellulose, NF                        89.000    Crospovidone, NF    14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        200.000    1B.    Terazosin HCl Anhydrous                        5.471    Microcrystalline Cellulose, NF                        167.529    Crospovidone, NF    14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        190.000    1C.    Terazosin HCl Anhydrous                        5.471    Lactose Monohydrate, NF                        174.529    Microcrystalline Cellulose, NF                        28.000    Sodium Starch Glycolate, NF                        14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        225.000    1D.    Terazosin HCl Anhydrous                        5.471    Lactose Monohydrate, NF                        174.529    Microcrystalline Cellulose, NF                        28.000    Croscarmellose Sodium, NF                        14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        225.000    1E.    Terazosin HCl Anhydrous                        5.471    Lactose Monohydrate, NF                        170.529    Microcrystalline Cellulose, NF                        28.000    Crospovidone, NF    14.000    Colloidal Silicon Dioxide, NF                        2.000    Talc USP            2.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        225.000    1F.    Terazosin HCl Anhydrous                        5.471    Corn Starch, NF, Pregelatinized                        174.529    Microcrystalline Cellulose, NF                        28.000    Crospovidone, NF    14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        225.000    1G.    Terazosin HCl Anhydrous                        5.471    Lactose Monohydrate, NF                        172.529    Microcrystalline Cellulose, NF                        28.000    Crospovidone, NF    14.000    Sodium Stearyl Fumarate, NF                        5.000    Total Capsule Fill Weight                        225.000    1H.    Terazosin HCl Anhydrous                        5.471    Dibasic Calcium Phosphate USP                        199.529    Microcrystalline Cellulose, NF                        28.000    Crospovidone, NF    14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        250.000    1I.    Terazosin HCl Anhydrous                        5.471    Lactose Monohydrate, NF                        194.529    Hydroxypropyl Methylcellulose                        8.000    Crospovidone, NF    14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        225.000    1J.    Terazosin HCl Anhydrous                        5.471    Lactose Monohydrate, NF                        197.529    Povidone USP        5.000    Crospovidone, NF    14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        225.000    1K.    Terazosin HCl Anhydrous                        5.471    Lactose Monohydrate, NF                        170.529    Microcrystalline Cellulose, NF                        28.000    Crospovidone, NF    14.000    Sodium Lauryl Sulfate USP                        2.000    Polyethylene Glycol, NF                        2.000    Hydrogenated Vegetable Oil NF                        3.000    Total Capsule Fill Weight                        225.000    1L.    Terazosin HCl Anhydrous                        5.471    Compressible, Sugar, NF                        194.529    Microcrystalline Cellulose, NF                        28.000    Crospovidone, NF    14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        245.000    1M.    Terazosin HCl Anhydrous                        5.471    Compressible Sugar, NF                        88.529    Confectioners Sugar, NF                        89.000    Crospovidone, NF    14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        200.000    1N.    Terazosin HCl Anhydrous                        5.471    Manitol, NF         167.529    Crospovidone, NF    14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        190.000    1O.    Terazosin HCl Anhydrous                        5.471    Dextrose, USP       174.529    Microcrystalline Cellulose, NF                        28.000    Sodium Starch Glycolate, NF                        14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        225.000    1P.    Terazosin HCl Anhydrous                        5.471    Lactose Monohydrate, NF                        174.529    Microcrystalline Cellulose, NF                        28.000    Croscarmellose Calcium, NF                        14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        225.000    1Q.    Terazosin HCl Anhydrous                        5.471    Lactose Monohydrate, NF                        168.529    Microcrystalline Cellulose, NF                        30.000    Polacrallin Potassium                        14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        225.000    1R.    Terazosin HCl Anhydrous                        5.471    Confectioners Sugar, NF                        174.529    Microcrystalline Cellulose, NF                        28.000    Crospovidone, NF    14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        225.000    1S.    Terazosin HCl Anhydrous                        5.471    Manitol, USP        172.529    Microcrystalline Cellulose, NF                        28.000    Crospovidone, NF    14.000    Sodium Stearyl Fumarate, NF                        5.000    Total Capsule Fill Weight                        225.000    1T.    Terazosin HCl Anhydrous                        5.471    Manitol, NF         199.529    Microcrystalline Cellulose, NF                        28.000    Crospovidone, NF    14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        250.000    1U.    Terazosin HCl Anhydrous                        5.471    Sorbitol, USP       194.529    Hydroxypropyl Methylcellulose                        8.000    Crospovidone, NF    14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        225.000    1V.    Terazosin HCl Anhydrous                        5.471    Sorbitol, USP       197.529    Povidone USP        5.000    Crospovidone, NF    14.000    Magnesium Stearate, NF                        3.000    Total Capsule Fill Weight                        225.000    1W.    Terazosin HCl Anhydrous                        5.471    Lactose Monohydrate, NF                        170.529    Microcrystalline Cellulose, NF                        28.000    Sodium Alginate     16.000    Hydrogenated Castor Oil                        5.000    Total Capsule Fill Weight                        225.000    ______________________________________

An accelerated stability study supports an expiration period of at leasttwo years for each of the formulations. After a single dose to a healthyhuman subject, each of the above formulations produces a plasmaconcentration of terazosin in the subject having both C_(max) and an AUCwithin the range from -20% to +25% of that produced by a referenceliquid-filled terazosin capsule.

We claim:
 1. A pharmaceutical solid-filled capsule dosage formcontaining a fill which consists of a pharmaceutically effective amountof terazosin in the form of a solid pharmaceutically acceptable salt, ora solvate thereof, and a solid carrier, which solid-filled capsuledosage form is therapeutically equivalent to a reference liquid-filledterazosin capsule containing a liquid fill which consists of anequivalent amount of terazosin and a non-aqueous liquid carrier, andwhich solid-filled capsule dosage form has an average dissolution at 30minutes for six capsules when tested according to U.S.P. Method II at 50r.p.m. in water of at least 85 percent of the label amount with noindividual capsule below 80 percent of the label amount after beingmaintained in a high density polyethylene bottle closed with a screw capat about 40° C. and 85 percent relative humidity for twelve weeks.
 2. Acapsule dosage form of claim 1 wherein the terazosin is present asanhydrous terazosin hydrochloride or terazosin hydrochloride dihydrate.3. A capsule dosage form of claim 2 wherein the average dissolution at30 minutes is at least 90 percent of the label amount with no individualcapsule below 80 percent of the label amount.
 4. A capsule dosage formof claim 2 wherein the average dissolution at 30 minutes is at least 95percent of an initial average dissolution.
 5. A dosage form of claim 2wherein the reference terazosin capsule comprises a liquid polyethyleneglycol as the non-aqueous liquid carrier.
 6. A dosage form of claim 5wherein the non-aqueous liquid carrier further comprises from 1 to 4percent by weight, based on the total weight of the capsule fill, ofglycerine.
 7. A dosage form of claim 2 wherein the reference terazosincapsule is a liquid-filled terazosin hydrochloride capsule which is thesubject of a U.S. Food and Drug Administration approved New DrugApplication.
 8. A dosage form of claim 7 wherein the reference terazosincapsule is a liquid-filled terazosin hydrochloride capsule which is thesubject of approved New Drug Application number N20347.
 9. A dosage formof claim 8 wherein the solid carrier comprises (a) from 70 to 100percent by weight of a diluent; (b) from 0 to 20 percent by weight of adisintegrant; and (c) 0 to 10 percent by weight of a lubricant.
 10. Adosage form of claim 9 wherein the solid carrier comprises (a) from 85to 97 percent by weight of a diluent; (b) from 1 to 10 percent by weightof a disintegrant; and (c) 0.2 to 5 percent by weight of a lubricant.11. A dosage form of claim 10 wherein the solid carrier comprises (a)from 90 to 97 percent by weight of a diluent; (b) from 1 to 5 percent byweight of a disintegrant; and (c) 0.5 to 2 percent by weight of alubricant.
 12. A dosage form of claim 9 wherein the diluent is amonosaccharide, a disaccharide or a polysaccharide.
 13. A capsule dosageform of claim 8 wherein the average dissolution at 30 minutes is atleast 90 percent of the label amount with no individual capsule below 80percent of the label amount.
 14. A capsule dosage form of claim 13wherein the average dissolution at 30 minutes is at least 95 percent ofan initial average dissolution.
 15. A dosage form of claim 13 whereinthe solid carrier comprises (a) from 70 to 100 percent by weight of adiluent; (b) from 0 to 10 percent by weight of a disintegrant; and (c) 0to 10 percent by weight of a lubricant.
 16. A method of administering atherapeutically effective amount of terazosin to a human subject, whichcomprises producing a plasma concentration of terazosirl in the subjecthaving both a maximum concentration (C_(max)) and an area under aplasma-concentration vs. time curve (AUC) within the range from -20% to+25% of that produced by a reference liquid-filled terazosin capsule,which contains an equivalent amount of terazosin in a non-aqueous liquidcarrier, by administering a solid-filled capsule dosage form whichconsists essentially of a pharmaceutically effective amount of terazosinin the form of a solid pharmaceutically acceptable salt, or solvatethereof, and a solid carrier to the subject.
 17. A method of claim 16wherein the reference liquid-filled capsule is the subject of approvedNew Drug Application number N20347.